This study aimed to investigate the molecular targets and anti-tumor mechanisms of cordycepin in gastric cancer (GC). Bioinformatics analysis was performed using the GSE65801 dataset to identify differentially expressed genes (DEGs) in GC. Potential cordycepin targets were screened from the CTD database, and the key gene was identified by intersecting these targets with GC DEGs and constructing a PPI network. The expression of fibronectin 1 (FN1) in GC was validated using public databases (TIMER, GEPIA and Ualcan) and in vitro experiments in GC cell lines (AGS and HGC-27). The functional effects of cordycepin, alone or in combination with FN1 overexpression, on cell proliferation (CCK8 and colony formation assay), apoptosis (flow cytometry), and the PI3K/AKT pathway (western blot) were assessed. A total of 649 DEGs were identified in GC and 336 potential targets of cordycepin were screened. FN1 was screened as a key intersection target of cordycepin and GC, and was found to be significantly upregulated in GC tissues and cells. High FN1 expression was associated with poor patient survival. Cordycepin treatment significantly inhibited the viability of GC cells and downregulated FN1 protein expression. Functionally, cordycepin suppressed cell proliferation and induced apoptosis by the inhibition of the PI3K/AKT pathway, and these effects were reversed by overexpression of FN1. In conclusion, cordycepin inhibited GC cell growth partially through the downregulation of FN1 and inactivation of the PI3K/AKT pathway, suggesting that FN1 was a novel potential target for cordycepin in the treatment of GC.
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